Type 2 diabetes is characterized by a two-to fourfold increased risk of cardiovascular disease. This is generally attributed to the adverse effects of hyperglycemia and oxidative stress on vascular biology. It has also been shown that patients with prediabetic conditions, such as impaired fasting glucose and impaired glucose tolerance, are at increased risk of cardiovascular disease as well (1). This result suggests that abnormalities in carbohydrate metabolism form a continuum that progressively worsens cardiovascular health; the first step of the adverse sequence of events that leads to the atherosclerotic process is thought to be endothelial dysfunction (2). Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis. In addition to providing a physical barrier between the vessel wall and lumen, the endothelium secretes a number of mediators that regulate platelet aggregation, coagulation, fibrinolysis, and vascular tone. The term “endothelial dysfunction” refers to a condition in which the endothelium loses its physiological properties: the tendency to promote vasodilation, fibrinolysis, and anti-aggregation. Endothelial cells secrete several mediators that can alternatively mediate either vasoconstriction, such as endothelin-1 and thromboxane A2, or vasodilation, such as nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor. NO is the major contributor to endothelium-dependent relaxation in conduit arteries, whereas the contribution of endothelium-derived hyperpolarizing factor predominates in smaller resistance vessels.

In patients with diabetes, endothelial dysfunction appears to be a consistent finding; indeed, there is general agreement that hyperglycemia and diabetes lead to an impairment of NO production and activity. The endothelium has a limited intrinsic capacity of self-repair, being built up by terminally differentiated cells with a low proliferative potential. That is why endothelial repair is accomplished through the contribution of circulating cells, namely endothelial progenitor cells (EPCs), in physiological and pathological conditions. In this review, we will outline the mechanisms of endothelial dysfunction in diabetes, the role of EPCs in cardiovascular homeostasis, and the implications of EPC alterations in diabetes and its complications (Fig. 1)(3).